EP0164311B1 - Wirksubstanzen enthaltende Hydrogelvorrichtungen, worin das Konzentrationsprofil der Wirksubstanz einen sigmoidalen Konzentrationsgradienten zur konstanten Freisetzung besitzt, deren Herstellung und Verwendung - Google Patents

Wirksubstanzen enthaltende Hydrogelvorrichtungen, worin das Konzentrationsprofil der Wirksubstanz einen sigmoidalen Konzentrationsgradienten zur konstanten Freisetzung besitzt, deren Herstellung und Verwendung Download PDF

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EP0164311B1
EP0164311B1 EP85810213A EP85810213A EP0164311B1 EP 0164311 B1 EP0164311 B1 EP 0164311B1 EP 85810213 A EP85810213 A EP 85810213A EP 85810213 A EP85810213 A EP 85810213A EP 0164311 B1 EP0164311 B1 EP 0164311B1
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active agent
hydrogel
swollen
bead
release
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EP0164311A2 (de
EP0164311A3 (en
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Ping I. Dr. Lee
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Novartis AG
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Ciba Geigy AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention relates to a hydrogel device containing an active agent which is released by diffusion to an aqueous medium upon contact therewith at a controlled rate for a predetermined period of time, a method for preparing such a device and a method of use of such a device to release the active agent into the aqueous medium.
  • Various devices are known in the art for the sustained release of an active agent.
  • monolithic devices for sustained release of agent wherein the agent is dispersed uniformly in a non-swellable homogeneous and imperforate polymer matrix where the agent dissolves in and permeates through the polymer itself are known.
  • Microporous devices in which the pores contain an active agent permeable liquid or gel medium such that the active agent preferentially dissolves in and permeates through the medium in the pores, are also known, as well as osmotic bursting devices wherein water is imbibed osmotically into active agent depots in a water permeable-active agent impermeable polymer matrix to rupture the depots serially.
  • osmotic bursting devices wherein water is imbibed osmotically into active agent depots in a water permeable-active agent impermeable polymer matrix to rupture the depots serially.
  • Characteristically, such devices release the active agent at a high initial rate which then drops off in
  • the only anomolous release pattern described and exemplified is that of an osmotic bursting device in which the bursting device was washed for 24 hours such that the initial release rate was decreased by 90% as described in Example 3B and Figure 10 of U.S. Patent No. 3,923,939.
  • Active agent releasing devices containing a swellable hydrogel matrix are also known in the art.
  • the active agent is uniformly distributed in the non-swollen, or glassy, hydrogel polymer.
  • the dry hydrogel swells as water penetrates the glassy matrix.
  • the boundary between the glassy phase and the swollen, or rubbery, phase of the hydrogel is known as the solvent front.
  • the active agent in the rubbery swollen phase of the hydrogel dissolves and diffuses through the swollen phase into the external aqueous environment.
  • the active agent is substantially incapable of diffusion to any significant extent in the glassy non-swollen phase of the hydrogel.
  • the rate of active agent transport into an aqueous environment is dependent upon a number of factors including the rate of penetration of the aqueous solvent front, the shape of the device, the diffusivity of the active agent in the swollen phase, the amount of active agent loading in the hydrogel matrix, the distance between the solvent front and the surface of the device, the rate of decrease of the surface area of the glassy phase during solvent penetration and the like. See, for example, Ping I. Lee, Polymer Communications, Vol. 24, p. 45-47 (1983).
  • the substantially continuous inflection point containing sigmoidal concentration distribution of the active agent from the surface to the core of the device thus increases in an increasing slope to an inflection point located between the surface and the core, and then increases in a decreasing slope from the inflection point to the core.
  • Such a sigmoidal curve containing profile cannot be obtained by merely washing an active agent loaded hydrogel device while in the fully swollen state, such as immediately after wet loading the active agent into the hydrogel and prior to drying the loaded device.
  • the removal of active agent for example by washing the surface thereof, generally results in a concentration profile which increases from the surface to the core in a decreasing slope.
  • Such an overall profile can be characterized as a "parabolic" concentration profile, as contrasted with a sigmoidal or "bell-shaped" concentration profile obtained according to the instant invention.
  • the parabolic concentration profile characteristically results in a time dependent release rate with a diminished initial rate.
  • a sigmoidal curve containing profile can be obtained by washing the surface of an active agent solute uniformly loaded hydrogel device which is initially in the non-swollen, or glassy, state, with a volatile swelling solvent for a time sufficient for the solvent to penetrate the outer surface of the device such that the device has an outer swollen, or rubbery, phase and an inner non-swollen, or glassy, phase or core, to thereby remove a portion of the active agent from the rubbery phase, and then rapidly removing the volatile solvent from the hydrogel device at a rate sufficient to immobilize the active agent in a stable concentration distribution in an increasing fashion from the surface to the core of the device whereby the gradient is in the form of a continuous inflection point containing sigmoidal concentration curve.
  • the swollen phase reverts to the non-swollen, glassy state. Accordingly, the desired concentration profile is obtained as a storage stable product, since the diffusivity of an active agent solute is characteristically at least several orders of magnitude less in a glassy hydrogel than in a swollen, or rubbery, hydrogel.
  • the process conditions and the nature of the swelling solvent are selected to provide the desired distribution, such that when the dried glassy hydrogel is subsequently placed in an aqueous hydrogel swelling environment of use, the improved device releases the active agent in a controlled substantially constant rate for a predetermined period of time.
  • Such process parameters of the active agent extraction include time and temperature. For any given temperature, the amount of penetration of the swelling solvent is time dependent. Similarly, the rate of diffusion of the active agent in the swollen portion of the hydrogel increases with increasing temperature, as does the rate of penetration of the solvent front. Thus, in some instances, accelerated extraction of a portion of the active agent by the use of elevated temperature conditions is desirable.
  • the temperature of extraction may vary widely, for example, between -20 to about 120°C, depending on the freezing and boiling point of the volatile swelling solvent chosen. If desired, superatmospheric presence conditions may be employed during the extraction step. Desirably, the temperature of the extraction step is chosen so as to be below the glass transition temperature of the loaded hydrogel. When the temperature of the extraction step is greater than the glass transition temperature of the loaded hydrogel, the diffusivity of the active agent in the unswollen portion of the device increases greatly.
  • the extraction temperature be between about -20°C up to about 120°C but not in excess of the glass transition temperature of the loaded hydrogel.
  • the glass transition temperature of loaded hydrogels is dependent in part on the nature of the hydrogel chosen, but is generally preferred between about 45°C to about 120°C or even higher. It is more preferred to use hydrogels having a loaded glass transition temperature of above 50°C and to conduct the extraction step at a temperature between about 10°C to 50°C.
  • the controlled extraction swells only the exterior of the device such that there is an unswollen core remaining in order to obtain the desired sigmoidal concentration profile.
  • the device is at least partially swollen during the profile modification process, preferably about 20 to 90 volume percent is at least partially swollen.
  • There is accordingly removed from the loaded hydrogel about 7 to 80 weight percent, preferably between 15 to 75 weight percent, active agent, based upon the amount of active agent originally present.
  • the sigmoidal concentration profile generated during the aforementioned extraction step be substantially retained during the solvent removal step in order to immobilize the active agent in this desired profile.
  • This can be accomplished by rapidly removing the swelling solvent from the swollen portion of the hydrogel matrix.
  • rapid removal in this context is meant that the rate of removal of the swelling solvent is substantially greater than the rate of diffusion of the active agent in the swollen portion of the hydrogel.
  • the desired rapid removal of the volatile swelling solvent can be effected by reducing the pressure of the system under iso-thermal or adiabatic conditions to remove the solvent by evaporation.
  • the degree to which the pressure is reduced will depend on the nature of the volatile swelling solvent and the temperature. Since it is desired to quickly remove the solvent so as to minimize active agent diffusion, a high vacuum is desirable.
  • the pressure is reduced to below 70 mm Hg, preferably lower than 10 mm Hg, most preferably below 0.1 mm Hg. Highly desirable is a reduction of pressure of 1 x 10 ⁇ 3 mm Hg and lower.
  • the reduction in pressure may be achieved under substantially adiabatic conditions, under moderate heating conditions or with cooling.
  • the hydrogels useful in this invention are generally all water swellable, but water insoluble polymers. Such polymers are, for instance, synthesized by free radical copolymerization of a water soluble vinyl monomer with a difunctional crosslinking agent; crosslinked poly-2-hydroxyethyl methacrylate and poly-vinylpyrrolidone are two of the most widely known and used hydrogels, but other water soluble monomers can also be used in the preparation of hydrogels as well as a large variety of comonomers and of crosslinking agents. Especially useful are hydrogels prepared by copolymerization with macromeric crosslinking agents, as described in U.S. 4,192,827. Other useful hydrogel compositions are described in U.S. 3,220,960; 3,520,949; and 3,503,942.
  • Water soluble vinyl monomers useful for the preparation of hydrogels include, but not exclusively, the hydroxyalkyl esters and amides of acrylic and methacrylic acid, such as 2-hydroxyethyl acrylate or methacrylate, 2- and 3-hydroxypropyl acrylate and methacrylate; 2,3-dihydroxypropyl methacrylate; compounds of structure where R and R' are hydrogen, methyl or ethyl and n is an integer from 2-50.
  • Hydroxyalkyl mono esters and diesters of maleic or fumaric acid, and their ethoxylated derivatives, like di-2-hydroxyethylmaleate and fumarate; and 2- and 3-hydroxypropylbutyl fumarate are similarly useful, as are hydroxy alkyl vinyl ethers, such as 2-hydroxyethyl vinyl ether and 4-hydroxybutyl vinyl ether.
  • These monomers can be used alone and in combination with each other, and may be copolymerized with suitable hydrophobic vinyl monomers, like styrene, acrylates and methacrylates, vinyl esters and vinyl ethers; maleates, fumarates and vinyl ethers require the presence of comonomers for polymerization to proceed.
  • suitable hydrophobic vinyl monomers like styrene, acrylates and methacrylates, vinyl esters and vinyl ethers; maleates, fumarates and vinyl ethers require the presence of comonomers for polymerization to proceed.
  • poly-vinyl alcohol in crosslinked or linear state as well as vinyl alcohol copolymers with ethylene, acrylate, vinylesters, and vinylpyrrolidone copolymers with vinylesters.
  • the crosslinking agent employed in making the hydrogel may be a di- or poly-functional vinyl compound of 200-10000 molecular weight and be present in the polymerizing mixture in amounts ranging from 0.1% (for low MW crosslinkers) to 60% (for high MW crosslinkers).
  • polyethylene oxide containing polycondensates such as polyurethanes from diisocynates and polyethylene oxide diols of 300 - 10000 MW; polyesters from diacids, diacid chlorides or anhydrides and polyethylene oxide diols of 300 - 10000 MW; unsaturated polyesters devised from maleic- or fumaric acid and polyethylene oxide diols and copolymerized with styrene or acrylic monomers to a crosslinked polymer; epoxy polymers derided from diepoxides and the 3-amino-propyl ethers of polyethylene oxide diols; polyamides from diacids, diacid chlorides and anhydrides and 3-aminopropyl ethers of polyethylene oxide diols of 300 - 10000 MW.
  • polyethylene oxide polymers can be prepared containing a large variety of co-reactants, having preferably at least 10% by weight of polyethoxy-units which can be classified as hydrogels.
  • Polycondensation hydrogels are described, for instance, in U.S. 3,822,238.
  • hydrogels prepared by free-radical initiated copolymerization of unsaturated polyesters based on maleic anhydride and alkylene diols with water-soluble vinyl monomers, vinyl pyrrolidone, 2-hydroxyethyl methacrylate, or hydroxy alkyl-vinylethers.
  • the hydrogels may also contain polysiloxane units, as described in U.S. patent 4,136,250, or contain perfluoro alkyl substituted side chains.
  • Other useful substrates include water swellable polymers derived from natural products, such as cellulose or proteins, for example reconstituted cellulose films, and hydroxy-ethyl cellulose, or gelatin and albumin derived polymers.
  • the term 'hydrogel' encompasses not only crosslinked water-swellable polymers, but also linear polymers which, like high molecular weight fully hydrolyzed polyvinyl alcohol, dissolve only with difficulty or not at all in the environment of use, forming in effect a linear hydrogel. Even water soluble polymers can be used in the context of this invention as long as they do not dissolve during the application of the process of the present invention.
  • hydrogel beads as they are obtained by suspension polymerization of hydroxyalkylacrylates or methacrylates, or N-vinyl-pyrrolidone containing mixtures. Such beads and the process for making them are described in U.S. Patent No. 4,224,427.
  • a hydrogel is defined as a polymer having an effective degree of swelling in water of at least 5% by weight water.
  • Drugs used to treat the body can be incorporated as the active agent in the carrier of this invention.
  • Drug is used herein in its broadest sense as including any composition of matter that will produce a pharmacological or biological response.
  • Suitable drugs for use in therapy according to this invention include, without limitations, those listed in Patent No. 3,732,865 (columns 10 and 11).
  • Drugs can be in various forms, such as uncharged molecules, components of molecular complexes, or non-irritating pharmacologically acceptable salts, e.g. the hydrochloride, hydrobromide, sulphate, phosphate, nitrate, borate, acetate, maleate, tartrate, salicylate, etc.
  • salts of metals, amines, or organic ations e.g. quaternary ammonium
  • simple derivatives of the drugs such as ethers, esters, amides, etc.
  • which have desirable retention and release characteristics but which are easily hydrolyzed by body pH, enzymes, etc. can be employed.
  • the amount of drug incorporated in the carrier varies widely depending on the particular drug, the desired therapeutic effect, and the time span for which it takes the drug to be released. Since a variety of carriers in a variety of sizes and shapes are intended to provide complete dosage regimes for therapy for a variety of maladies, there is no critical upper limit on the amount of drug incorporated in the carrier. The lower limit, too, will depend on the activity of the drug and the span of its release from the carrier. Thus, it is not practical to define a range for the therapeutically effective amount of drug to be released by the carrier.
  • Preferred drugs to be incorporated according to the present invention are those designed for long-term treatment so that multiple daily doses can be avoided, for example, anabolics, e.g. methandrostenolone; analgesics, e.g. acetylsalicylic acid, phenylbutazone or methadone; androgens, e.g. methyltestosterone; antibiotics, e.g. rifampin; antidepressants, e.g. imipramine or maprotiline; antidiabetics; e.g. phenformin; anticonvulsives, e.g. carbamazepine; antihistamines, e.g.
  • anabolics e.g. methandrostenolone
  • analgesics e.g. acetylsalicylic acid, phenylbutazone or methadone
  • androgens e.g. methyltestosterone
  • antibiotics
  • tripelennamine tripelennamine
  • antihypertensives e.g. hydralazine
  • antiinfectives e.g. trimethoprim
  • antiparasitics e.g. nifurtimox
  • antiparkinson agents e.g. levodopa
  • antiphlogistics e.g. naproxen antitussives, e.g. benzonatate
  • appetite depressants e.g. mazindol
  • bronchodilators e.g. fenoterol
  • coronary dilators e.g. fenalcomine
  • corticoids e.g. dexamethasone
  • cytostatics e.g.
  • floxuridine floxuridine
  • diuretics e.g. hydrochlorothiazide
  • hypnotics e.g. glutethimide
  • neuroleptics e.g. reserpine or thioridazine
  • psycho-analeptics e.g. methylphenidate
  • tranquilizers e.g. diazepam
  • uricosurics e.g. sulfinpyrazone
  • vasodilators e.g. isoproterenol.
  • fragrances or food flavors include bactericides, fungicides, insecticides, nematocides, and herbicides.
  • the active agent be sufficiently soluble in the aqueous environment of use, i.e. a solute for the aqueous environment, so as to diffuse through the swollen hydrogel upon aqueous activation to an extent sufficient so as to achieve the desired effect.
  • the active agent is substantially solid in the dry state. This further reduces the amount of diffusion which may occur when desired the active agent profile is obtained in the glassy state and thereby enhances the storage stability of the sigmoidal concentration profile.
  • the active agent loaded hydrogel starting materials for the instant invention ordinarily possess a uniform active agent concentration and are in the glassy or non-swollen state.
  • Such starting materials are known or are easily obtained, for example, by immersing the hydrogel in solutions of the active agents in solvents or solvent mixtures which are swelling agents for the hydrogel.
  • Suitable swelling agents include water, lower alkanols, lower alkanones, methylene chloride, dimethylformamide, dimethylsulfoxide, water-lower alkanol mixtures, water-lower alkanone mixtures and the like, to remove the swelling solvent under ambient or reduced pressure.
  • Volatile swelling solvents useful for removing a portion of the active agent from the glassy or non-swollen loaded hydrogel include water, lower alkanols of up to 5 carbon atoms, lower alkanones of up to 5 carbon atoms, methylene chloride and miscible mixtures thereof.
  • the hydrogel device is not critical, and may be in the form of rounded cylindrical tablets, corneal lenses, rods, cubes, sheets, tubes, and the like, the hydrogel device is preferably generally spherical in shape, e.g. in the form of a bead. Preferably, such beads may vary in size between about 0.01 mm to about 20 mm in diameter depending upon the desired application.
  • aqueous fluid such as water, body fluids, including gastric fluid, tear fluid, intestinal fluid and the like, rain water, soil moisture and sea water
  • the water diffuses into the device, swelling the same from the surface inwardly.
  • the active agent diffuses from the swelling and swollen region to the environment.
  • the release rate is thus dependent upon the rate of active agent in the swollen region and the like.
  • the improved device containing the active agent in the sigmoidal concentration profile
  • the active agent is released from the device in a controlled continuous manner by diffusion.
  • At least 40 weight percent of the active agent released upon such actuation is released at substantially a constant, or zero-order rate.
  • the improved devices of the instant invention are especially advantageous in the release of active agents where the effective dose thereof is relatively close to the dose above which side effects may arise. Unlike prior art systems having a release rate which is initially high, for example approaching or exceeding that which undesirable side effects may be manifested, and then drops off to below the optimum effective dose release rate, the instant devices can be designed to release active agent at the optimum release rate while minimizing the risk of overdose at any time. While such release rate characteristics are in theory attainable by covering a loaded hydrogel with a rate controlling membrane, such membranes tend to crack or rupture due to the swelling characteristics of the hydrogel substrate.
  • the improved device is in the form of a hydrogel bead, wherein the core, substantially uniformly loaded with active agent, extends from the center of the device outwardly to comprise about 1% to about 60% of the radius of the bead, the sigmoidal concentration gradient of the active agent extends to cover about 99% to about 30% of the radius, and there may be present a substantially uniform at least partially depleted outer portion constituting 0 to about 10% of the radius of the bead.
  • the inflection point may be offset up to about 30%, preferably not more than 20%, and most preferably not more than 15% from the center of the gradient in either radial direction. Where there is a substantially uniform at least partially depleted outer portion, there is preferably present no more than 10 weight percent per unit volume of active agent, as compared to the core concentration of active agent.
  • Figure 1a depicts a representative active agent concentration profile according to the instant invention, where 0 is the center of the device and D is the surface thereof, segment 0A represents the radius of the core, segment AC represents the radial segment containing the sigmoidal concentration gradient, the point B represents the inflection point thereof, and the optionally present segment CD represents the at least partially depleted outer portion of the device.
  • Figure 1b depicts a representative active agent profile generated by merely washing a uniformly loaded fully swollen hydrogel device, where 0 is the center of the device, C' is the surface thereof, the segment OA' represents the radius of the core and the segment A'C' represents the parabolic concentration profile.
  • compositions in the following examples are expressed in weight percentage unless otherwise noted.
  • Hydrogel beads used in this example were prepared by free radical suspension polymerization of a monomer mixture containing 70% of a 2-hydroxyethylmethacrylate (HEMA) and 30% of a polymeric crosslinking agent (PX) derived from poly(tetramethyleneoxide) of average molecular weight 2,000 by end capping the isophoronediisocyanate followed by reaction with excess HEMA as described in U.S. Patents 4,177,056 and 4,224,427. After the completion of polymerization, these beads were filtered and extracted in a Soxhlet with ethanol for 24 hours before being dried and fractionated into standard mesh sizes for use in the present invention. Said dry hydrogel beads exhibit a glass transition temperature (Tg) of about 116°C as determined by differential scanning colorimetry (DSC), an equilibrium water swelling of about 25%, and an equilibrium ethanol swelling of about 49%.
  • Tg glass transition temperature
  • DSC differential scanning colorimetry
  • Such a process immobilizes a sigmoidal drug concentration profile with an apparent inflection point within the dry hydrogel matrix in contrast to the uniform drug concentration profile in the untreated control as demonstrated by the experimentally determined SEM x-ray microprobe chlorine scans for orprenolol HCl across the cross-sections of both the 20-minute extracted and the unextracted control beads (shown in Figures 2a and 2b).
  • Figure 3a shows that the t50's (time to reach 50% release) are further extended (more than doubled) by the present invention as compared to that of the control and time-lags (obtained by extrapolating the linear release region to the time axis) of up to 0.13 hours are obtained by the present invention as compared to the total absence of a time-lag in the unextracted control.
  • the effect of controlled-extraction time on the oxprenolol HCl loading is shown in Figure 3b. Only about 10% of the drug loading is removed at an extraction time as long as 30 minutes.
  • This example illustrates the storage stability of systems prepared according to the present invention.
  • Example 1 was repeated except that 7.5 gm of -16+18 mesh beads was used for the initial loading of oxprenolol HCl and only the 20 and 30-minute controlled-extracted beads in addition to the unextracted control were prepared. The amounts of loading solution and extracting solvent used were proportionally increased according to Example 1.
  • This example illustrates the importance of applying the controlled-extraction step of the present invention to a dry, glassy, drug loaded hydrogel matrix in order to generate the desired inflection point, time lag, and constant-rate release region in the cummulate release profile.
  • Example 1 The hydrogel composition and oxprenolol HCl loading procedure of Example 1 were utilized. Immediately after equilibrating the hydrogel beads in the drug solution, a portion of the swollen, loaded beads were subjected to the controlled-extraction step in water for 30 minutes and subsequently freeze-dried under high degree of vacuum. Another portion of the swollen, loaded beads were dried before subjected to the controlled-extraction in water for 30 minutes and the subsequent freeze-drying step as described in Example 1.
  • the in-vitro oxprenolol HCl release from the latter showed a characteristic inflection point, time lag, and a substantial constant-rate region in the cumulative release curve, however the former showed only a slight reduction in the initial release rate as compared to the control, and the inflection point, time lag and constant-rate region were distinctively absent.
  • This example illustrates the need of a freeze-drying process instead of drying at a temperature near or above the glass transition temperature of the swollen drug-polymer composite in order to ensure the occurrance of the desired inflection point, time lag, and constant-rate region in the cumulative release profile.
  • Said hydrogel beads exhibit a glass transition temperature of about 115°C, an equilibrium water swelling of about 20%, and an equilibrium ethanol swelling of about 45%.
  • the hydrogel beads so prepared were subjected to the same purification, oxprenolol HCl loading and drying steps as in Example 1. The dry, loaded beads were controlled-extracted in water for 30 minutes. One portion of the extracted beads was immediately freeze-dried as in Example 1, whereas another portion was dried in a vacuum oven at an elevated temperature of 50°C.
  • the in-vitro oxprenolol HCl release from the freeze-dried portion showed a characteristic inflection point, time lag, and a substantial constant-rate region in the cumulative release curve, however the portion dried at 50°C showed only a slight reduction in the initial release rate as compared to the control, and the inflection point, time lag, and constant-rate region were distinctively absent.
  • This example illustrates the effect of different solvent used in the controlled-extraction step on the oxprenolol HCl release from another glassy hydrogel composition.
  • Hydrogel beads used in this example were prepared by free radical suspension polymerization of a monomer mixture containing 21% HEMA, 12% PX (defined in Example 1), 12% N-vinylpyrrolidone (NVP), 27.5% ethyl hexyl-actylate (EHA), and 27.5% methyl methacrylate () according to U.S. 4,224,427.
  • Said hydrogel beads exhibit a glass transition temperature of about 99°C, an equilibrium water swelling of about 12%, and an equilibrium ethanol swelling of about 60%
  • hydrogel beads so prepared were subjected to the purification, loading, and drying steps according to Example 1 except that 50% oxprenolol HCl loading solution was prepared in methanol.
  • the dry, loaded beads containing 37.4% of uniformly distributed drug were either controlled-extracted in water for 30 minutes or in acetone for 10 minutes before being freeze-dried as in Example 1.
  • the in-vitro release of oxprenolol HCl from these controlled-extracted beads are compared with that of the unextracted control in Figure 5.
  • This example illustrates the versatility of the present invention by varying the polymer morphology, mesh size, type of drug, and method of loading.
  • Hydrogel beads used in this example were prepared by free radical suspension polymerization of a monomer mixture identical to that of Example 5 with 50% of polypropylene glycol (MW 3,600) dissolve in the monomer mixture as diluent. After the completion of polymerization, these beads were filtered and extracted in a Soxhlet with ethanol for 3 days to remove the diluent and residual monomer before being dried and fractionated into standard mesh sizes for use in the present invention. Said hydrogel beads exhibit a glass transition temperature of about 99°C, an equilibrium water swelling of about 10%, and an equilibrium ethanol swelling of about 72%.
  • the in-vitro release of diclofenac sodium from these controlled-extracted beads showed a characteristic inflection point, a time-lag of about 2 minutes, and a constant-rate release region up to 60% of the total release as compared to the total absence of these characteristics in the unextracted control.
  • the t50's (time to reach 50% release) of these controlled-extracted beads were increased to five times that of the unextracted control.
  • Example 1 The process of Example 1 was repeated on hydrogel sheets containing different active agents.
  • the in-vitro releases from systems prepared according to the present invention showed characteristic inflection points, time-lags, and extended constant-rate release regions in contrast to the total absence of these characteristics in the unextracted controls.
  • This example illustrates the necessity to utilize the present invention in a glassy hydrogel system.
  • oxprenolol HCl of particle size between about 0.5 to 5 ⁇ m were dispersed in a viscous solution containing 37 parts of ethylene vinylacetate copolymer (30% vinylacetate) and 52 parts of xylene.
  • the rubbery ethylene vinylacetate copolymer used here has a glass transition temperature of about -25°C with negligible water swelling.
  • the above mentioned viscous solution was cast on a glass plate and subsequently air dried to form a film having a thickness of 0.2 mm and a 23% oxprenolol HCl loading.
  • About 1.5 cm2 of the said loaded ethylene vinylacetate film was controlled-extracted in acetone for 10 minutes before being freeze-dried as in Example 1.

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Claims (20)

  1. Wirksubstanz enthaltendes Diffusions-Hilfsmittel zur kontrollierten Freisetzung, das eine quellbare Hydrogel-Matrix in nichtgequollenem Zustand umfaßt, die von einer gelösten Wirksubstanz mit einer stabilen Konzentrationsverteilung die mit einem Gradienten normal zur Oberfläche des Hilfsmittels und zwischen der Oberfläche und dem Kern desselben zunimmt, durchsetzt ist, wobei der Gradient die Form einer im wesentlichen kontinuierlichen, einen Wendepunkt enthaltenden S-förmigen Kurve aufweist, sodaß das Hilfsmittel, wenn es in ein wässeriges hydrogelquellendes Milieu gegeben wird, die Wirksubstanz in einer kontrollierten kontinuierlichen Weise durch Diffusion während einer vorbestimmten Zeitspanne in das wässerige Milieu freisetzt.
  2. Hilfsmittel nach Anspruch 1, das in Form eines Kügelchens vorliegt.
  3. Hilfsmittel nach Anspruch 2, wobei das Kügelchen einen Durchmesser von etwa 0,01 mm bis etwa 20 mm hat.
  4. Hilfsmittel nach Anspruch 1, wobei die Wirksubstanz ein Arzneimittel ist.
  5. Hilfsmittel nach Anspruch 3, wobei die Wirksubstanz ein Arzneimittel ist.
  6. Hilfsmittel nach Anspruch 1, wobei mindestens 40 Gew.-% der Wirksubstanz im wesentlichen mit einer Geschwindigkeit nullter Ordnung freigesetzt wird.
  7. Hilfsmittel nach Anspruch 1, wobei mindestens 50 Gew.-% der Wirksubstanz im wesentlichen mit einer Geschwindigkeit nullter Ordnung freigesetzt wird.
  8. Hilfsmittel in Form eins Kügelchens nach Anspruch 2, wobei der Kern im wesentlichen gleichmäßig mit Wirksubstanz beladen ist und sich von der Mitte des Kügelchens nach außen bis zu etwa 1 bis etwa 60 % des Radius des Kügelchens erstreckt; der S-förmige Konzentrationsgradient der Wirksubstanz sich vom Kern nach außen erstreckt, um etwa 99 bis etwa 30 % des Radius des Kügelchens zu umfassen, und der Rest bis zu etwa 10 % des äußersten Teiles des Radius bis zur Oberfläche des Kügelchens, mindestens teilweise von Wirksubstanz befreit ist.
  9. Hilfsmittel nach Anspruch 5, wobei der äußerste Teil des Radius des Kügelchens nicht mehr als 10 pro Volumeneinheit an Wirksubstanz im Vergleich mit der Wirksubstanzkonzentration im Kern enthält.
  10. Hilfsmittel nach Anspruch 1, wobei das Hydrogel in dem wässerigen verwendeten Quellmilieu im wesentlichen unlöslich ist.
  11. Hilfsmittel nach Anspruch 10, wobei das Hydrogel ein vernetztes, in Wasser quellbares Polymer ist.
  12. Verfahren zur Herstellung eines Hilfsmittels nach Anspruch 1, welches
    a) Waschen der Oberfläche eines mit Wirksubstanz gleichmäßig beladenen Hydrogelhilfsmittels, welches im nichtgequollenen oder glasartigen Zustand ist, mit einem flüchtigen quellend wirkenden Lösungsmittel während einer für das Lösungsmittel ausreichenden Zeit, damit es die äußere Oberfläche des Hilfsmittels durchdringt, sodaß das Hilfsmittel eine äußere, gequollene oder gummiartige Phase und einen inneren nichtgequollenen oder glasartigen Kern aufweist, um dadurch einen Teil der Wirksubstanz aus der gummitartigen Phase zu extrahieren und einen Wirksubstanz-Konzentrationsgradienten in Form einer im wesentlichen kontinuierlichen, einen Wendepunkt enthaltenden, S-förmigen Kurve zu erzeugen;
    b) Entfernen des flüchtigen quellend wirkenden Lösungsmittels aus dem gequollenen Teil des Hilfsmittels mit einer ausreichenden Geschwindigkeit um das Wirksubstanzprofil in Form der kontinuierlichen, einen Wendepunkt enthaltenden, S-förmigen Kurve zu immobilisieren und
    c) Wiedergewinnung des entstandenen nicht gequollenen Hilfsmittels, umfaßt.
  13. Verfahren nach Anspruch 12, wobei die Extraktionsstufe a) zwischen -20°C bis zu etwa 120°C durchgeführt wird, jedoch ohne Überschreitung der Glasumwandlungstemperatur des mit Wirksubstanz beladenen Hydrogels.
  14. Verfahren nach Anspruch 12, wobei die Stufe b) der Entfernung des flüchtigen Lösungsmittels bei einem Druck unter 70 mm Hg durchgeführt wird.
  15. Verfahren nach Anspruch 14, wobei die Stufe b) der Entfernung des flüchtigen Lösungsmittels unter im wesentlichen adiabatischen Bedingungen durchgeführt wird.
  16. Verfahren nach Anspruch 12, wobei zwischen etwa 15 bis 98 Vol.-% des Hilfsmittels mindestens teilweise durch das flüchtige quellend wirkende Lösungsmittel gequollen ist.
  17. Verfahren nach Anspruch 12, wobei zwischen etwa 7 bis 80 Gew.-% der Wirksubstanz, bezogen auf die Menge der Wirksubstanz in dem beladenen Hilfsmittel, aus dem Hilfsmittel während der Extraktionsstufe a) entfernt werden.
  18. In einem Verfahren zur Lieferung einer gelösten Wirksubstanz in ein wässeriges Milieu, welches kein Menschen- oder Tierkörper ist, die Verbesserung, bei der Wirksubstanz aus einem Hilfsmittel nach Anspruch 1 freigesetzt wird.
  19. Verfahren nach Anspruch 18, worin die Wirksubstanz ein Arzneimittel ist.
  20. Verfahren nach Anspruch 19, worin das Hilfsmittel in Form eines Kügelchens vorliegt.
EP85810213A 1984-05-10 1985-05-07 Wirksubstanzen enthaltende Hydrogelvorrichtungen, worin das Konzentrationsprofil der Wirksubstanz einen sigmoidalen Konzentrationsgradienten zur konstanten Freisetzung besitzt, deren Herstellung und Verwendung Expired - Lifetime EP0164311B1 (de)

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US06/608,756 US4624848A (en) 1984-05-10 1984-05-10 Active agent containing hydrogel devices wherein the active agent concentration profile contains a sigmoidal concentration gradient for improved constant release, their manufacture and use

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8802149B2 (en) 1996-12-31 2014-08-12 Novartis Pharma Ag Systems and processes for spray drying hydrophobic and hydrophilic components
WO2018005600A1 (en) * 2016-06-28 2018-01-04 Trustees Of Tufts College Compositions and methods for delivery of active agents

Families Citing this family (120)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4749576A (en) * 1984-05-10 1988-06-07 Ciba-Geigy Corporation Active agent containing hydrogel devices wherein the active agent concentration profile contains a sigmoidal concentration gradient for improved constant release, their manufacture and use
JPS61218517A (ja) * 1985-03-25 1986-09-29 Bio Materiaru Yunibaasu:Kk 経皮吸収製剤
FR2585246A1 (fr) * 1985-07-26 1987-01-30 Cortial Procede d'obtention de formes pharmaceutiques solides a liberation prolongee
US4794002A (en) * 1985-11-01 1988-12-27 Monsanto Company Modified polymeric surfaces and process for preparing same
JPH0643851B2 (ja) * 1986-03-13 1994-06-08 大同メタル工業株式会社 軸受ユニット
US4983400A (en) * 1986-06-16 1991-01-08 Merck & Co., Inc. Controlled release combination of carbidopa/levodopa
US4780236A (en) * 1986-06-20 1988-10-25 Kiwi Brands, Inc. Lavoratory cleansing block containing polyethylene gycol disteatrate, guar gum and sodium chloride
US4743248A (en) * 1986-08-11 1988-05-10 Alza Corporation Dosage form for delivering acid sensitive beneficial agent
GB8620845D0 (en) * 1986-08-28 1986-10-08 Reckitt & Colmann Prod Ltd Treatment of textile surfaces
EP0297650A1 (de) * 1987-06-26 1989-01-04 Duphar International Research B.V Zusammensetzungen mit Freisetzung nullter Ordnung und Verfahren zu ihrer Herstellung
US5219575A (en) * 1987-06-26 1993-06-15 Duphar International Research B.V. Compositions with controlled zero-order delivery rate and method of preparing these compositions
US4910015A (en) * 1987-10-19 1990-03-20 Massachusetts Institute Of Technology Surface-active polysiloxanes and drug releasing materials thereof
GB8801863D0 (en) * 1988-01-28 1988-02-24 Fulmer Yarsley Ltd Pharmaceutical formulations with controlled drug release
US6440457B1 (en) * 1993-05-27 2002-08-27 Alza Corporation Method of administering antidepressant dosage form
CA2212165A1 (en) 1995-02-10 1996-08-15 Matthew A. Bergan Method and device for administering analgesics
US5945125A (en) * 1995-02-28 1999-08-31 Temple University Controlled release tablet
GB9703673D0 (en) * 1997-02-21 1997-04-09 Bradford Particle Design Ltd Method and apparatus for the formation of particles
US6039968A (en) * 1997-06-24 2000-03-21 Hoechst Marion Roussel Intravaginal drug delivery device
DE19843904A1 (de) * 1998-09-24 2000-03-30 Basf Ag Feste Dosierungsform mit polymerem Bindemittel
DE19843903A1 (de) * 1998-09-24 2000-03-30 Basf Ag Feste Dosierungsform mit copolymerem Bindemittel
US6706283B1 (en) * 1999-02-10 2004-03-16 Pfizer Inc Controlled release by extrusion of solid amorphous dispersions of drugs
US7943162B2 (en) * 1999-10-21 2011-05-17 Alcon, Inc. Drug delivery device
BR0016708A (pt) * 1999-12-23 2002-10-08 Pfizer Prod Inc Forma de dosagem de droga baseada em hidrogel
US20030086972A1 (en) * 2000-08-09 2003-05-08 Appel Leah E. Hydrogel-driven drug dosage form
GB0027357D0 (en) * 2000-11-09 2000-12-27 Bradford Particle Design Plc Particle formation methods and their products
WO2003009774A2 (en) 2001-07-23 2003-02-06 Alcon, Inc. Ophthalmic drug delivery device
EP1385452B1 (de) * 2001-07-23 2006-09-13 Alcon, Inc. Vorrichtung zur freisetzung eines ophthalmischen arzneimittels
CA2464653C (en) * 2001-10-29 2011-10-18 Therics, Inc. System for manufacturing controlled release dosage forms, such as a zero-order release profile dosage form manufactured by three-dimensional printing
GB0216562D0 (en) 2002-04-25 2002-08-28 Bradford Particle Design Ltd Particulate materials
US9339459B2 (en) 2003-04-24 2016-05-17 Nektar Therapeutics Particulate materials
GB0310636D0 (en) * 2003-05-08 2003-06-11 Nektar Therapeutics Uk Ltd Particulate materials
MXPA05011343A (es) 2003-05-08 2005-12-12 Nektar Therapeutics Uk Ltd Materiales particulados.
AU2004258857A1 (en) * 2003-07-10 2005-02-03 Alcon, Inc. Ophthalmic drug delivery device
US20060246109A1 (en) * 2005-04-29 2006-11-02 Hossainy Syed F Concentration gradient profiles for control of agent release rates from polymer matrices
US8182840B2 (en) * 2005-09-27 2012-05-22 Tissue Tech, Inc. Amniotic membrane preparations and purified compositions and therapy for scar reversal and inhibition
US8187639B2 (en) 2005-09-27 2012-05-29 Tissue Tech, Inc. Amniotic membrane preparations and purified compositions and anti-angiogenesis treatment
US7858609B2 (en) 2005-11-28 2010-12-28 Marinus Pharmaceuticals Solid ganaxolone formulations and methods for the making and use thereof
US8246973B2 (en) 2006-06-21 2012-08-21 Advanced Cardiovascular Systems, Inc. Freeze-thaw method for modifying stent coating
CN101528830A (zh) 2006-07-10 2009-09-09 麦德医像公司 超弹性环氧水凝胶
EP2056818B1 (de) 2006-08-11 2011-05-25 The Johns Hopkins University Zusammensetzungen und verfahren für nervenschutz
CN102887900B (zh) 2006-09-22 2015-04-29 药品循环公司 布鲁顿酪氨酸激酶的抑制剂
KR101257550B1 (ko) 2007-09-10 2013-04-24 칼시메디카, 인크 세포내 칼슘을 조절하는 화합물
EP2227635A2 (de) 2007-12-03 2010-09-15 Medipacs, Inc. Fluiddosiervorrichtung
JP5782377B2 (ja) 2008-08-27 2015-09-24 カルシメディカ，インク． 細胞内カルシウムを調節する化合物
DK2421901T3 (en) 2009-04-24 2016-01-11 Tissue Tech Inc Compositions comprising HC-HA complex, and methods of use thereof
US9238102B2 (en) 2009-09-10 2016-01-19 Medipacs, Inc. Low profile actuator and improved method of caregiver controlled administration of therapeutics
US7741330B1 (en) 2009-10-12 2010-06-22 Pharmacyclics, Inc. Pyrazolo-pyrimidine inhibitors of Bruton's tyrosine kinase
US9500186B2 (en) 2010-02-01 2016-11-22 Medipacs, Inc. High surface area polymer actuator with gas mitigating components
ES2602475T3 (es) 2010-04-15 2017-02-21 Tracon Pharmaceuticals, Inc. Potenciación de la actividad anticáncer por terapia de combinación con inhibidores de la vía BER
US8754219B2 (en) 2010-04-27 2014-06-17 Calcimedica, Inc. Compounds that modulate intracellular calcium
JP6112486B2 (ja) 2010-04-27 2017-04-12 カルシメディカ，インク． 細胞内カルシウムを調節する化合物
NZ789041A (en) 2010-06-03 2023-09-29 Pharmacyclics Llc The use of inhibitors of bruton’s tyrosine kinase (btk)
CA2809830C (en) 2010-08-27 2019-09-10 Calcimedica, Inc. Compounds comprising n-acyl-2-amino-1,3-thiazole for modulating intracellular calcium
WO2012061556A1 (en) 2010-11-03 2012-05-10 Flugen, Inc. Wearable drug delivery device having spring drive and sliding actuation mechanism
MX350838B (es) 2011-02-11 2017-09-18 Grain Proc Corporation * Composicion de sal.
WO2012149486A1 (en) 2011-04-28 2012-11-01 Tissuetech, Inc. Methods of modulating bone remodeling
WO2012170905A1 (en) 2011-06-10 2012-12-13 Tissuetech, Inc. Methods of processing fetal support tissues, fetal support tissue powder products, and uses thereof
JP6330118B2 (ja) 2011-09-13 2018-05-30 ファーマサイクリックス エルエルシー ベンダムスチンと組み合わせたヒストンデアセチラーゼ阻害剤の製剤とその使用
US8377946B1 (en) 2011-12-30 2013-02-19 Pharmacyclics, Inc. Pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine compounds as kinase inhibitors
EP3326627A1 (de) 2012-01-06 2018-05-30 Abide Therapeutics, Inc. Carbamatverbindungen sowie herstellung und verwendung davon
CA2906274A1 (en) 2012-03-14 2013-09-19 Medipacs, Inc. Smart polymer materials with excess reactive molecules
KR20200017549A (ko) 2012-06-04 2020-02-18 파마싸이클릭스 엘엘씨 브루톤 타이로신 키나아제 저해제의 결정 형태
KR102236805B1 (ko) 2012-07-11 2021-04-05 티슈테크, 인코포레이티드 Hc-ha/ptx3 복합체를 함유하는 조성물 및 이의 사용 방법
CA2885828C (en) 2012-09-28 2021-04-27 University Of Washington Through Its Center For Commercialization Ureido-thiophenyl derivatives, compositions thereof and methods for preventing, treating and/or protecting against sensory hair cell death
US9512116B2 (en) 2012-10-12 2016-12-06 Calcimedica, Inc. Compounds that modulate intracellular calcium
WO2015054283A1 (en) 2013-10-08 2015-04-16 Calcimedica, Inc. Compounds that modulate intracellular calcium
WO2015084998A1 (en) 2013-12-05 2015-06-11 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
EP3134418A4 (de) 2014-04-23 2018-01-03 The Research Foundation for The State University of New York Schnelle und effiziente reaktion zur bioorthogonalen reaktion und borhaltige, zusammen damit nützliche heterocyclen
TW201603818A (zh) 2014-06-03 2016-02-01 組織科技股份有限公司 組成物及方法
US10080877B2 (en) 2014-07-25 2018-09-25 Warsaw Orthopedic, Inc. Drug delivery device and methods having a drug cartridge
US9775978B2 (en) 2014-07-25 2017-10-03 Warsaw Orthopedic, Inc. Drug delivery device and methods having a retaining member
US9839644B2 (en) 2014-09-09 2017-12-12 ARKAY Therapeutics, LLC Formulations and methods for treatment of metabolic syndrome
US9359316B1 (en) 2014-11-25 2016-06-07 Concentric Analgesics, Inc. Prodrugs of phenolic TRPV1 agonists
AU2016215023B2 (en) 2015-02-06 2019-12-19 Fred Hutchinson Cancer Center Compounds and methods for preventing or treating sensory hair cell death
US10227333B2 (en) 2015-02-11 2019-03-12 Curtana Pharmaceuticals, Inc. Inhibition of OLIG2 activity
US20160243288A1 (en) 2015-02-23 2016-08-25 Tissuetech, Inc. Apparatuses and methods for treating ophthalmic diseases and disorders
IL254007B1 (en) 2015-02-27 2024-04-01 Curtana Pharmaceuticals Inc Inhibition of OLIG2 activity
NZ734446A (en) 2015-03-03 2022-12-23 Pharmacyclics Llc Pharmaceutical formulations of bruton’s tyrosine kinase inhibtor
MA41828A (fr) 2015-03-27 2018-01-30 Pharmacyclics Llc Co-cristaux d'un inhibiteur de la tyrosine kinase de bruton
MA41827A (fr) 2015-03-27 2018-01-30 Pharmacyclics Llc Formes solvatées d'un inhibiteur de la tyrosine kinase de bruton
EP3294731A4 (de) 2015-05-11 2018-10-24 Abide Therapeutics, Inc. Verfahren zur behandlung von entzündungen oder neuropathischem schmerz
TWI720984B (zh) 2015-05-20 2021-03-11 美商帝聖工業公司 用於防止上皮細胞增生及上皮-間質轉移之組合物及方法
WO2017040617A1 (en) 2015-08-31 2017-03-09 Pharmacyclics Llc Btk inhibitor combinations for treating multiple myeloma
US10076650B2 (en) 2015-11-23 2018-09-18 Warsaw Orthopedic, Inc. Enhanced stylet for drug depot injector
EP4253412A3 (de) 2015-12-16 2023-11-22 The Walter and Eliza Hall Institute of Medical Research Hemmung von cytokininduziertem sh2-protein in nk-zellen
CA3008576A1 (en) 2016-01-19 2017-07-27 Janssen Pharmaceutica Nv Formulations/compositions comprising a btk inhibitor
WO2017125423A1 (en) 2016-01-19 2017-07-27 Janssen Pharmaceutica Nv Formulations/compositions comprising a btk inhibitor
TW201733600A (zh) 2016-01-29 2017-10-01 帝聖工業公司 胎兒扶持組織物及使用方法
US10851123B2 (en) 2016-02-23 2020-12-01 Concentric Analgesics, Inc. Prodrugs of phenolic TRPV1 agonists
JP7049683B2 (ja) 2016-04-04 2022-04-07 シノピア バイオサイエンシーズ，インク． トラピジルを使用する錐体外路症候群の処置
EP3463576A4 (de) 2016-05-25 2020-01-15 Concentric Analgesics, Inc. Prodrugs von phenolischen trpv1-agonisten in kombination mit lokalanästhetika und vasokonstriktoren für verbesserte lokalanästhesie
WO2017205762A1 (en) 2016-05-27 2017-11-30 Pharmacyclics Llc Inhibitors of interleukin-1 receptor-associated kinase
WO2017205769A1 (en) 2016-05-27 2017-11-30 Pharmacyclics Llc Inhibitors of interleukin-1 receptor-associated kinase
WO2017205766A1 (en) 2016-05-27 2017-11-30 Pharmacyclics Llc Inhibitors of interleukin-1 receptor-associated kinase
US10549081B2 (en) 2016-06-23 2020-02-04 Warsaw Orthopedic, Inc. Drug delivery device and methods having a retaining member
CN116332886A (zh) 2016-07-18 2023-06-27 广州瑞安博医药科技有限公司 用于治疗或预防与痛风或高尿酸血症相关的症状的化合物、组合物和方法
CN109843868A (zh) 2016-08-26 2019-06-04 科泰纳制药公司 Olig2活性的抑制
US10434261B2 (en) 2016-11-08 2019-10-08 Warsaw Orthopedic, Inc. Drug pellet delivery system and method
DK3541807T3 (da) 2016-11-16 2021-12-06 H Lundbeck As Krystallinsk form af en magl-inhibitor
TN2019000148A1 (en) 2016-11-16 2020-10-05 Abide Therapeutics Inc Pharmaceutical formulations
KR20200086257A (ko) 2017-09-01 2020-07-16 유니버시티 오브 워싱톤 감각 모 세포 사멸 예방 또는 치료용 화합물의 결정질 형태
US11685722B2 (en) 2018-02-28 2023-06-27 Curtana Pharmaceuticals, Inc. Inhibition of Olig2 activity
EP3830078A4 (de) 2018-07-27 2022-03-30 Concentric Analgesics, Inc. Pegylierte prodrugs von phenolischen trpv1-agonisten
JP2022516057A (ja) 2018-12-31 2022-02-24 バイオメア フュージョン，エルエルシー メニン－ｍｌｌ相互作用の不可逆的阻害剤
US20220265630A1 (en) 2019-03-15 2022-08-25 Unicycive Therapeutics Inc. Nicorandil derivatives
WO2021214550A1 (en) 2020-04-21 2021-10-28 H. Lundbeck A/S Synthesis of a monoacylglycerol lipase inhibitor
EP4263542A1 (de) 2020-12-16 2023-10-25 Biomea Fusion, Inc. Kondensierte pyrimidinverbindungen als inhibitoren der menin-mll-interaktion
CA3204457A1 (en) 2021-01-06 2022-07-14 Ben SESSA Mdma in the treatment of alcohol use disorder
CA3218884A1 (en) 2021-05-11 2022-11-17 David Nutt Therapeutic aminoindane compounds and compositions
WO2022256720A2 (en) 2021-06-03 2022-12-08 Arcadia Medicine, Inc. Enantiomeric entactogen compositions and methods of their use
US20230120115A1 (en) 2021-08-11 2023-04-20 Biomea Fusion, Inc. Covalent inhibitors of menin-mll interaction for diabetes mellitus
TW202313004A (zh) 2021-08-20 2023-04-01 美商拜歐米富士恩股份有限公司 Ｍｅｎｉｎ－ｍｌｌ相互作用之不可逆抑制劑的結晶形式
WO2023027966A1 (en) 2021-08-24 2023-03-02 Biomea Fusion, Inc. Pyrazine compounds as irreversible inhibitors of flt3
WO2023039240A1 (en) 2021-09-13 2023-03-16 Biomea Fusion, Inc. IRREVERSIBLE INHIBITORS OF KRas
WO2023086341A1 (en) 2021-11-09 2023-05-19 Biomea Fusion, Inc. Inhibitors of kras
WO2023129667A1 (en) 2021-12-30 2023-07-06 Biomea Fusion, Inc. Pyrazine compounds as inhibitors of flt3
WO2023139163A1 (en) 2022-01-19 2023-07-27 Awakn Ls Europe Holdings Limited 1,3-benzodioxole esters and their therapeutic use
WO2023156565A1 (en) 2022-02-16 2023-08-24 Awakn Ls Europe Holdings Limited Bridged ring compounds and their therapeutic use as cns agents
WO2023235618A1 (en) 2022-06-03 2023-12-07 Biomea Fusion, Inc. Fused pyrimidine compounds as inhibitors of menin
US20240010649A1 (en) 2022-07-06 2024-01-11 Oppilan Pharma Limited Crystalline forms of an s1p receptor modulator

Family Cites Families (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH468192A (de) * 1964-06-19 1969-02-15 Ciba Geigy Verfahren zur Herstellung von Arzneimitteln in Perlenform
IT1050353B (it) * 1966-01-06 1981-03-10 Ceskoslovenska Akademie Ved Supporti per sostanze biologigamente attive
US3660563A (en) * 1966-07-26 1972-05-02 Nat Patent Dev Corp Water soluble entrapping of a drug
US3660071A (en) * 1966-07-26 1972-05-02 Nat Patent Dev Corp Water soluble entrapping of a pesticide
US3577512A (en) * 1968-10-11 1971-05-04 Nat Patent Dev Corp Sustained release tablets
US3576760A (en) * 1969-06-13 1971-04-27 Nat Patent Dev Corp Water soluble entrapping
DE2031871C3 (de) * 1970-06-27 1974-06-27 Roehm Gmbh, 6100 Darmstadt Überzugsmasse für Arzneiformen
GB1394990A (en) * 1971-08-12 1975-05-21 Hydrophilics Int Inc Copolymers and compositions containing copolymers
US4056496A (en) * 1972-10-02 1977-11-01 Corneal Sciences, Inc. Hydrogels and articles made therefrom
US4070348A (en) * 1973-07-25 1978-01-24 Rohm Gmbh Water-swellable, bead copolymer
US4007258A (en) * 1973-09-10 1977-02-08 Union Corporation Sustained release pesticidal composition
US4178361A (en) * 1973-09-10 1979-12-11 Union Corporation Sustained release pharmaceutical composition
CH621561A5 (en) * 1974-01-14 1981-02-13 Ceskoslovenska Akademie Ved Process for producing a bromocyan-activated, hydrophilic, polymeric carrier for biologically active compounds in dried form
US3923939A (en) * 1974-06-07 1975-12-02 Alza Corp Process for improving release kinetics of a monolithic drug delivery device
US4177056A (en) * 1974-06-27 1979-12-04 Ciba-Geigy Corporation Water-insoluble hydrophilic copolymers used as carriers for medicaments and pesticides
US4248855A (en) * 1976-08-27 1981-02-03 Hydrophilics International, Inc. Pharmaceutical base salts
US4164560A (en) * 1977-01-05 1979-08-14 Folkman Moses J Systems for the controlled release of macromolecules
US4304591A (en) * 1978-01-25 1981-12-08 Ciba-Geigy Corporation Water-insoluble hydrophilic copolymers used as carriers for medicaments and pesticides
CA1125698A (en) * 1978-03-09 1982-06-15 Masaru Yoshida Process for preparing a polymer composition
US4267295A (en) * 1979-02-09 1981-05-12 Syntex (U.S.A.) Inc. Polymeric compositions and hydrogels formed therefrom
US4357312A (en) * 1981-07-16 1982-11-02 The Children's Hospital Medical Center Method of making prolonged release body
IL70071A (en) * 1982-11-01 1987-12-31 Merrell Dow Pharma Multilayered sustained release pharmaceutical tablets having non-uniform distribution of active ingredient
US4564364A (en) * 1983-05-26 1986-01-14 Alza Corporation Active agent dispenser
GB8319766D0 (en) * 1983-07-22 1983-08-24 Graham N B Controlled release device

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8802149B2 (en) 1996-12-31 2014-08-12 Novartis Pharma Ag Systems and processes for spray drying hydrophobic and hydrophilic components
WO2018005600A1 (en) * 2016-06-28 2018-01-04 Trustees Of Tufts College Compositions and methods for delivery of active agents
US11090702B2 (en) 2016-06-28 2021-08-17 Trustees Of Tufts College Compositions and methods for delivery of active agents

Also Published As

Publication number Publication date
CA1246447A (en) 1988-12-13
AU4221685A (en) 1985-11-14
EP0164311A2 (de) 1985-12-11
ES542948A0 (es) 1986-01-01
NZ212030A (en) 1988-01-08
IL75129A (en) 1989-08-15
DK205185A (da) 1985-11-11
US4624848A (en) 1986-11-25
JPS619A (ja) 1986-01-06
DK205185D0 (da) 1985-05-09
FI851801L (fi) 1985-11-11
PT80416B (en) 1987-04-16
PT80416A (en) 1985-06-01
FI851801A0 (fi) 1985-05-08
DE3582193D1 (de) 1991-04-25
ES8603273A1 (es) 1986-01-01
EP0164311A3 (en) 1987-06-03
ATE61731T1 (de) 1991-04-15
IL75129A0 (en) 1985-09-29
PH24100A (en) 1990-03-05
GR851114B (de) 1985-11-25
AU583507B2 (en) 1989-05-04
ZA853511B (en) 1985-12-24

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